DESCRIPTION: The most important consequence of lung disease is hypoxemia resulting in impaired oxygen supply to thetissues, diminishing organ function. This research program continues its commitment to understanding the[unreadable] causes and effects of hypoxemia in health and disease. Three of the five projects address this at the level of[unreadable] the skeletal muscles. A fourth deals with cardiac consequences of hypoxia, and a fifth with neural plasticity in[unreadable] hypoxia. The same five project'leadersare proposed as in the current cycle (years 26-30), lending continuity[unreadable] to a productive program. However, experimental approaches have evolved to focus more onfundamental[unreadable] mechanisms of the hypoxic response. Yet there are also studies proposed to link these back to humans as a[unreadable] function of age and disease, making for an integrated approach to the problem of hypoxia. Project 1 (Wagner)[unreadable] focuses on the basic molecular mechanisms of muscle angiogenesis in response to hypoxia in health and[unreadable] disease; Project 2 (Mathieu-Costello) uses modern morphometric methods to assess regional myocardialOz[unreadable] availability and the impact of chronic hypoxia and aging on this; Project 3 (Richardson) examines the effects[unreadable] of aging on human muscle structure and function using integrative methods ranging from macroscopic[unreadable] imaging to molecular biological; Project 4 (Powell) addresses the effects of hypoxia on neural function[unreadable] involved in ventilatory control, integrating molecular and physiological tools; Project 5 (Hogan) investigates[unreadable] the role of Oaavailability on single muscle fiber function in vitro using a combination of imaging, functional,[unreadable] and molecular methods. The projects interact extensively,many formally asjoint efforts between project[unreadable] leaders with overlapping interests, and are supported by three cores (Tissue Imaging and Morphometry;[unreadable] Molecular Biology; Administration). Our collective goals are to better understand how Oatransport between[unreadable] the environment and the mitochondria of several key organs is regulated as a function of aging and disease,[unreadable] and in turn, how hypoxia itself modulates its own availability and thereby affects organ function in these same[unreadable] conditions.